1-241500602-TGAGAGAGAGAGAGAGAGA-TGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGA

Position:

• chr1-241500602-TGAGAGAGAGAGAGAGAGA-TGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGA

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_000143.4(FH):​c.1237-13_1237-12insTCTCTCTCTCTCTCTCTC variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (4 hom., cov: 0)
  • Exomes 𝑓: 0.0014 (9 hom.)
  • Failed GnomAD Quality Control
• Consequence: FH NM_000143.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.993

Genes affected

FH (HGNC:3700): (fumarate hydratase) The protein encoded by this gene is an enzymatic component of the tricarboxylic acid (TCA) cycle, or Krebs cycle, and catalyzes the formation of L-malate from fumarate. It exists in both a cytosolic form and an N-terminal extended form, differing only in the translation start site used. The N-terminal extended form is targeted to the mitochondrion, where the removal of the extension generates the same form as in the cytoplasm. It is similar to some thermostable class II fumarases and functions as a homotetramer. Mutations in this gene can cause fumarase deficiency and lead to progressive encephalopathy. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP6: Variant 1-241500602-T-TGAGAGAGAGAGAGAGAGA is Benign according to our data. Variant chr1-241500602-T-TGAGAGAGAGAGAGAGAGA is described in ClinVar as [Likely_benign]. Clinvar id is 1692239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 533 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FH	NM_000143.4	c.1237-13_1237-12insTCTCTCTCTCTCTCTCTC		splice_polypyrimidine_tract_variant, intron_variant		ENST00000366560.4	NP_000134.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FH	ENST00000366560.4	c.1237-13_1237-12insTCTCTCTCTCTCTCTCTC		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000143.4	ENSP00000355518	P1

Frequencies

GnomAD3 genomes AF: 0.00399 AC: 533 AN: 133734 Hom.: 4 Cov.: 0

Gnomad AFR AF: 0.00456

Gnomad AMI AF: 0.00462

Gnomad AMR AF: 0.00297

Gnomad ASJ AF: 0.0162

Gnomad EAS AF: 0.000651

Gnomad SAS AF: 0.00197

Gnomad FIN AF: 0.00508

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00354

Gnomad OTH AF: 0.00281

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00140 AC: 1904 AN: 1355580 Hom.: 9 Cov.: 48 AF XY: 0.00134 AC XY: 906 AN XY: 674866

Gnomad4 AFR exome AF: 0.00278

Gnomad4 AMR exome AF: 0.000724

Gnomad4 ASJ exome AF: 0.00431

Gnomad4 EAS exome AF: 0.000186

Gnomad4 SAS exome AF: 0.000421

Gnomad4 FIN exome AF: 0.00307

Gnomad4 NFE exome AF: 0.00136

Gnomad4 OTH exome AF: 0.00181

GnomAD4 genome AF: 0.00398 AC: 533 AN: 133824 Hom.: 4 Cov.: 0 AF XY: 0.00374 AC XY: 239 AN XY: 63840

Gnomad4 AFR AF: 0.00455

Gnomad4 AMR AF: 0.00296

Gnomad4 ASJ AF: 0.0162

Gnomad4 EAS AF: 0.000652

Gnomad4 SAS AF: 0.00197

Gnomad4 FIN AF: 0.00508

Gnomad4 NFE AF: 0.00354

Gnomad4 OTH AF: 0.00278

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Jun 07, 2021

- -

FH-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 19, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs144131869; hg19: chr1-241663902;